Project Summary The use of volatile organic solvents as drugs of abuse is a significant and understudied health problem. These agents, also termed abused inhalants, are voluntarily inhaled or ?huffed? for their intoxicating effects and their use is especially prevalent among children and adolescents. Volatile solvents are legal and are found in a wide variety of household and commercial products including glues, adhesives and paint thinners. Exposure to these compounds is associated with a variety of adverse effects ranging from reduced social and academic performance, brain abnormalities and a sudden-death syndrome resulting from solvent-induced cardiac arrhythmia. Although abused inhalants produce ethanol-like signs of intoxication, the sites and mechanisms of action that underlie these effects are largely unknown. Research carried out under this NIDA funded grant established that abused inhalants such as toluene have important and specific actions on channels implicated in mediating the actions of a wide variety of drugs of abuse. In addition, we have shown that toluene reduces glutamatergic EPSCs in mPFC neurons via both direct actions on ionotropic GluRs and via a novel endocannabinoid mediated depression of signaling. A brief exposure of adolescent animals to toluene vapor robustly enhances the AMPA/NMDA ratio in mesolimbic DA neurons while having little effect on those that project to the prefrontal cortex. Moreover, the changes in DA neuron excitability were dependent on the output of prefrontal cortex suggesting an important role for this region in regulating the rewarding effects of abused inhalants. Recent results show that an acute exposure to toluene produces changes in mPFC neuron activity that vary depending on the sub-region, layer, projection target and age at exposure while repeated exposures induce a conditioned place preference associated with selective alterations in mPFC-NAc signaling. Reversing these alterations with chemogenetic approaches blocked the expression of CPP. In this renewal application, we propose three specific aims to further extend these exciting findings and examine the role of NAc neurons in toluene reward. Aim 1 will determine how exposure to toluene vapor affects the excitability and synaptic signaling of medium spiny neurons (MSNs) in the nucleus accumbens using both in vitro and in vivo approaches. Studies in Aim 2 will develop and use a novel model of toluene vapor self-administration to examine effects of voluntary toluene exposure on NAc MSN physiology. Aim 3 will test the hypothesis that self-administration of toluene vapor is blocked by manipulating the activity of NAc MSNs and their specific excitatory inputs from mPFC sub-regions. Overall, the results from these studies will fill an important gap in our knowledge regarding the actions of abused inhalants on the addiction neurocircuitry.